The genetic and non-genetic risk factors for primary biliary cirrhosis (PBC) have not yet been well investigated. As a result, the cause and pathogenesis of this chronic cholestatic liver disease remain unclear, and PBC continues to diminish the quality of life and decrease the life expectancy of many women, the main sufferers of this disease. In an effort to begin deciphering the genetic susceptibility and environmental risks of this complex autoimmune disease, we created the Mayo Clinic PBC Genetic Epidemiology (MCPGE) registry and biospecimen repository. This research resource currently comprises 410 PBC patients and 290 clinic-based controls individually matched for age (+2.5 years), sex, race, and state of residence. The concept of genetic predisposition to PBC is well established and widely accepted. Recently, a mouse model of PBC (NOD.c3c4) was used to identify an autoimmune biliary disease 1 (Abd1) locus. Despite progress, the genetic susceptibility to PBC, its non-genetic risk factors, as well as the way in which they interact to result in disease, await meticulous investigation. In this application, we would like to test the hypothesis that genetic variants (i.e. single nucleotide polymorphisms - SNPs) of the human immunome (i.e. the sum of known genes that encode the essential components of the immune system) and human genes homologous to the murine Abd1 locus are associated with PBC, by utilizing 500 cases and 500 controls of the MCPGE research resource. The Specific Aims of this proposal are: Aim 1 we will genotype the cases and controls using a custom SNP array of 847 immune genes (10,734 SNPs) and perform genetic association analyses; Aim 2 we will genotype the cases and controls with a custom SNP array of 250 human genes homologous to murine Abd1 locus (4,337 SNPs) and perform genetic association analyses; Aim 3 we will: (a) verify proposed risk factors of PBC (i.e. smoking, urinary tract infection, hormone replacement therapy) and assess novel putative risk factors (i.e. second hand smoking, water source, pesticides exposure); and (b) test for interaction between environmental exposure and genetic variants found to be associated with PBC risk in Aims 1 and 2. This study will have significant translational impact because it will identify genetic polymorphisms and nongenetic risk factors associated with PBC. By dissecting the genetic and environmental risks that are relevant for further study in PBC, this investigation will become the foundation for future risk assessment and disease prevention strategies as well as for basic research studies exploring implicated mechanisms and potentially leading to novel treatments for this devastating disease. Public Health Relevance: This translational study seeks to examine the susceptibility of humans to Primary Biliary Cirrhosis (PBC), a chronic autoimmune liver disease that diminishes quality of life and shortens life expectancy. Using our recently developed Mayo Clinic PBC Genetic Epidemiology (MCPGE) Registry and Biospecimen Repository, we propose studies to identify genetic variants and nongenetic (i.e. environmental) risk factors that contribute to PBC. If successful, this study will pave the road to improved prevention and innovative therapies for this devastating disease.